1. Field of the Invention
This invention is in the field of organic chemistry. More particularly it relates to a steroselective synthesis of oxygen-containing heterocyclic organic compounds and materials formed by this process. In one application, this process is used to prepare the antimalarial agent known as qinghaosu or arteminisin.
2. Background References
There are two distinct bodies of art of interest. One is the art relating to the chemical reactions employed in the steroselective synthesis. The other is the art relating to antimalarials to which this process can advantageously be applied.
A key step in the chemical synthesis is the ozonolysis of a vinylsilane which leads transiently to an .alpha.-hydroperoxyaldehyde, and thence to the desired product. The only reference of which we are aware which involves ozonolysis of a vinylsilane and can lead to an .alpha.-hydroxyperoxyaldehyde is that of George Buchi, et al, Journal of the American Chemical Society, Vol 100:1, 294 (1978). This reference illustrates the use of this reaction but arrives at different ring structures than called for herein.
The antimalarial qinghaosu has been used in China in the form of crude plant products since at least twenty years, there has been an extensive interest in this material. This has led to an elucidation of its structure as ##STR3## The chemical name arteminisin has been applied to the material. This name will be used in this application to identify the material.
The carbons in the arteminisin structure have been numbered as set forth above. When reference is made to a particular location in a tetracyclic compound of this general type it will, whenever possible, be based on the numbering system noted in this structure. For example, the carbon atoms bridged by the peroxide bridge will always be identified as the "4" and "6" carbons, irrespective of the fact that this invention can involve materials having different bridge length structures in which these carbons would properly be otherwise numbered.
References to arteminisin and to some derivatives of it include the May 31, 1985 review article by Daniel L. Klayman appearing in Science, Vol 228, 1049, (1985); and the article appearing in the Chinese Medical Journal, Vol 92, No. 12, 811 (1979). Two syntheses of arteminisin have been reported in the literature by Wei-Shan Zhou, Pure and Applied Chemistry, Vol 58(5), 817, (1986); and by G. Schmid et al, Journal of the American Chemistry Society, Vol 105(3), 624 (1983). Neither of these syntheses employs the ozonolysis as set forth herein.
The interest in arteminisin has prompted a desire for an effective and efficient method for its total synthesis so as to eliminate the need to recover the material from crude vegetable preparations. A total synthesis method will also permit this family of compounds to be radiolabeled in nonlabile positions. This invention serves to satisfy these needs.